PT84832B - PROCESS FOR THE PREPARATION OF NEW ALQUENAMIDE DERIVATIVES - Google Patents

Abstract

The invention concerns novel N-[4(Z)-2-substituted-6-(4-o-hydroxyphenyl-1,3 dioxan-cis-5-yl) hexenoyllsulphon- amide derivatives of formula I of value as therapeutic agents. Typically R' is a branched (3-6C)alkyl, trifluoromethyl or phenyl radical as defined hereinafter and R² is alkyl, benzyl or phenyl.

The invention also discloses salts of the formula I compounds as well as pharmaceutical compositions containing the compounds and processes for the production of the compounds.

Description

Description

The present invention relates to new alkenamide derivatives and more particularly to the new derivatives of U- / 4 (Z) -6- (4-o-hydroxy-phenyl-1. 3-dioxan-cis-5-yl) hexe noil_7-guifonamide that antagonize one or more of the actions of thromboxane A _g (still known as TXAg ”) and that are valuable as therapeutic agents · The invention also relates to new iV * ^A pharmaceutical compositions containing one of the new derivatives and processes intermediates for the preparation of new amide derivatives.

It is known that it is a powerful blood platelet agglutinator and a powerful vasoconstrictor. 0

Z / *

TXA £ is also a powerful constrictor of the smooth muscle of the bronchi and trachea. That is why TXAg can be associated with a wide variety of disease situations, for example

heart disease such as myocardial infarction, angina, cerebrovascular diseases such as transient cerebral ischemia, migraine and collapse, peripheral vascular diseases such as atherosclerosis, microangiopathy, hypertension and blood clotting defects due to lipid imbalance, and pulmonary diseases such as embolism, bronchial asthma, bronchitis,

Pneumonia, dyspnoea and emphysema · Consequently, it is admitted that compounds that antagonize the actions of TXAg may therefore

M has therapeutic value in preventing or treating any one or more of the aforementioned diseases or any other disease situations in which it is desirable to antagonize the actions of TXAg.

In the European Stop application with the number 94239 of the applicant, several derivatives of the 4-phenyl-1,3-dioxan-5-yl-alkenic acid of the formula Z are described which have cis relative stereochemistry at the positions 4 and 5 of the ring of dioxin in which Ra and Rb are hydrogen, alkyl, haloalkyl, alkenyl and arylalkyl or aryl or optionally substituted, Rc is hydroxy, alkoxy or alkanesulfonamido, n is 1 or 2, A is ethylene or vinylene, Y is polymethylene (C2-C5) optionally substituted by alkyl and on the benzene ring B supports one or two optional substituents · We have now discovered (and here lies the basis in our invention) that a new group of amide derivatives of the formula Z where in the benzene ring B is o -hydroxy-phenyl, n is 1, A is cis-vinylene, Y is ethylene and Rc is sulfonamido, as defined above, have a particularly useful TXAg antagonism.

According to the present invention,

N- / ~ 4 (Z) -6- (4-o-hydroxy-phenyl-1,3-dioxan-5-yl) hexenoyl / '

-sulfonamide of formula I · i

wherein R1 is trifluoro-methyl, branched alkyl or is phenyl which optionally supports a substituent selected from halogen, cyano, nitro, trifluoro-methyl and alkoxy (θ ^ -θ ^) and R ² is alkyl (OpCg), benzyl or phenyl , the latter of which may optionally support a halogen substituent, (C 1-4) alkyl, alkoxy (^ - ^ 4), trifluoro-methyl, cyano or nitro; and the substituents at positions 4 and 5 of the dioxane ring in formula I and 0 substituent R have relative useful stereochemistry; and the respective pharmaceutically acceptable salts are also provided

It should be noted that the compounds of formula I have asymmetric carbon atoms and can exist and be isolated in racemic and optically active forms · The invention encompasses racemic forms and any of the optically active forms (or mixtures thereof) that are susceptible to antagonize one or more of the actions of the TXAg, the process of preparing individual optical isomers (for example, by synthesis from optically active materials, or by resolving in a racemic manner) and the way of determining properties Taa ₂ antagonists using one or more of the following standard tests ·

In the chemical formulas presented in this specification, although it presents a particular configuration, it does not necessarily correspond to the abso configuration

fight"

A particular significance for R when it is branched (C ^-G ^) alkyl is, for example, isopropyl, isobutyl, sec-butyl or t-butyl ·

A particular significance for a substitute

2 “optional tuinte that may be present in R or R when ^z is phenyl or in R when benzyl, as defined above, is for example: fluoro, chloro or bromo in the case of halogen; methyl or ethyl in the case of (C1 -C4) alkyl; and methoxy or ethoxy in the case of alkoxy

The particular pharmaceutically acceptable salts of sulfonamide derivatives of formula I are for example: salts of alkali metals and alkaline earth metals, such as the lithium, sodium, potassium, magnesium and calcium salts; salts with organic amines and quaternary bases that form physiologically acceptable cations, such as the salts of methylamine, dimethylamine, trimethylamine, ethylene diamine, piperidine, morpholine, pyrrolidine, piperazine, ethanolamine, triethanolamine; U-methyl-glucamine, tetra-methyl-ammonium hydroxide and benzyl-trimethyl-ammonium hydroxide.

~ / 1

Specific meanings for R that are of special interest include, for example, isopropyl, t-butyl, trifluoro-methyl and phenyl which optionally supports a fluoro, chloro, bromo, cyano, nitro, trifluoro-methyl or methoxy substitute »!

~ 1

A preferred meaning for R is isopropyl, t-butyl, trifluoro-methyl, 2-chloro-phenyl, 2-cyano-phenyl, 3- (trifluoro-methyl) -phenyl, 4-chloro-phenyl, 4-cyano-phenyl or 4-nitro-phenyl »

- 4 ιΓ-

" 2

A preferred meaning for R when it is alkyl (0-j-Og), is for example methyl or ethyl ·

Specific compounds of formula I of particular interest are shown in the following examples ·

The compounds of formula I can prepare *

by conventional processes of organic chemistry well known in the art of preparing structurally analogous compounds · Such processes are presented as an additional aspect of the invention and are illustrated by the following processes in which B and R have any of the above meanings:

a) An aldehyde of formula II is reacted with a Wittig reagent of the formula:

R ' ₃ P = CH. (CH ₂ ) ₂ .C0.N-.S0 ₂ R ² m ⁺ where R' is alkyl or aryl (especially phenyl) and

M ⁺ is a cation, for example an alkali metal cation, such as lithium, sodium or potassium cation · ®m in general the process provides compounds of formula I in which the substituents adjacent to the double bond have predominantly the necessary cis stereochemistry , that is, a 'Z' isomer. Any undesirable ó 'isomer can be removed by standard purification processes such as crystallization or chromatography.

The process is conveniently carried out in a suitable solvent or diluent, for example, in an aromatic solvent such as benzene, toluene or chloro-benzene, in an ether such as 1,2-dimethoxy-ethane, t-butyl-methyl ether, dibutyl ether or tetrahydrofuran, in dimethyl sulfoxide or tetra-methyl

- 5 non-sulfone; or in a mixture of one or more solvents or diluents. The process is generally carried out at a temperature between -80 ° C θ 40 ° 0, but it is conveniently carried out near ambient temperature, in a range between 0 and 35 ° C.

(b) A phenol derivative of formula III is deprotected

wherein R "is a suitable protecting group, for example alkyl (C₁ to _C₆)} (such as methyl or ethyl), acyl (such as acetyl, benzoyl, methanesulfonyl or toluene-sulfonyl £) there, tetrahydropyran-2-ion or trimethyl-silyl ·

The exact deprotection conditions depend on the nature of the protecting group R * * · So, for example, when it comes to methyl or ethyl, deprotection can be carried out by heating with sodium thio-ethoxide in a suitable solvent ( such as Ν, Ν-dimethyl-formamide or 1,5-dimethyl-3,4,

5,6-tetrahydro-2 (1H) -pyrimidinone) at a temperature between 60 and 160 ° C. Alternatively, an ethyl or methyl protecting group can be removed by reaction with lithium diphenyl phosphide in a suitable solvent (such as tetrahydrofuran or t-butyl methyl ether) at a temperature between 0 and 60 ° C ° C. When the protecting group is acyl, it can be removed, for example, by hydrolysis in the presence of a base (such as sodium or potassium hydroxide) in a suitable aqueous solvent (such as aqueous alkanol) at a temperature comprising

-hydropyran-2-yl, can be removed for example, by treatment with a strong acid such as trifluoroacetic acid and when it is trimethyl silyl it can be removed for example, by reaction with tetra-butyl ammonium fluoride aqueous or sodium fluoride, using a conventional process · (c) For a compound of formula I where 3 is different from trifluoro-methyl, an erythro diol derivative of formula IV is reacted

where one of Q and Q is hydrogen and the other is hydrogen or a group of the formula CRaRb '0H (where Ha and Rb are the same or different alkyls, with an aldehyde of the formula R .CO.H, where

R has the same meaning as R with the exception of trifluoro-methyl, or with an acetal, or hemi-acetal or a corresponding hydrate · aldehyde / or its hydrate, or its acetal or hemi-acetal or an alkanol (0 ^ - 0 ^) (such as methanol | or ethanol) _7 is generally used in excess · the reaction is generally carried out in the presence of a catalyst hydrochloric acid, hydrobromic acid, sulfaric acid, phosphoric acid, methanesulfonic acid, acid & -toluenesulfonic acid, or an acidic resin, conveniently

ff xylene or an ether, for example tetrahydrofuran, dibutyl ether, t-butyl methyl ether or 1,2-dimethoxy ethane, and at a temperature between 0 and 80 ° C.

The starting materials of formula IV in which Q and Q are both hydrogen can be obtained, for example, under mild hydrolysis catalyzed by acid, or by alcoholisation of the dioxane ring of a compound of formula V

wherein Ra and Rb are both alkyl, such as methyl or ethyl. Hydrolysis or alcoholysis is normally carried out at a temperature between 10 and 80 ° C using an aqueous mineral acid such as hydrochloric acid, an alkanol (such as ethanol or 2-propanol) or an ether (such as such as tetrahydrofuran), as a solvent.

The starting materials of formula IV in which one of Q and Q is hydrogen and the other is a group of the formula -GRaRb.OH are intermediates, as mentioned above, for the: formation of starting materials of formula IV in which Q and Q are both hydrogen. However, said intermediates are not normally isolated or characterized. Consequently, the invention also provides as a process:

(d) A modification of process (c) which consists in reacting a compound of formula V

where one of 8a and Sb is hydrogen, methyl or ethyl and the other is zz 6 methyl or ethyl, with an excess of aldehyde of the formula R .CO.H or a corresponding acetal, hemi-acetal or hydrate, in the presence of an acid catalyst (such as one of the above) conveniently at a temperature between 10 and 80 ° C for example, and optionally in the presence of a suitable solvent or diluent (such as those mentioned above)

The starting materials for use in the foregoing processes can be prepared by the general procedures of known organic chemistry for the preparation of structurally related compounds, for example, by analogy with the processes described in the European patent application with publication number 94239.

The protected phenol derivatives of the formula UI can be prepared, for example, using a procedure analogous to the process in paragraph (a) above, using an aldehyde analogous to formula II but in which the phenol group has been protected as the group R * ¹ · The starting materials of formula V can be obtained, for example, using procedures similar to those described in the European patent application with no. of publication 94239.

The necessary Wittig reagents can

obtained, for example, by conventional processes, for example, by treating the corresponding phosphonium halides, with a strong base such as sodium hydride, lithium diisopropyl amide, potassium t-butoxide or butyl- lithium · They usually form in situ. immediately before carrying out the previous condensation process (a) ·

The necessary starting materials of formula III can be obtained conveniently, for example, by phasing the corresponding protected acid of formula VI to react

_z 2 with a sulfonamide of the formula HgN.SOgR and with a suitable dehydrating agent, for example, Ν, ΙΤ-dicielo-hezil-carbo-diimide, optionally together with an organic base, for example,

4- (dimethylamino) pyridine, in the presence of a suitable solvent or diluent, for example, methylene chloride at a temperature between 10 - 50 ° C, but preferably close to room temperature.

Alternatively, a recative acid derivative of the formula VI _} can be reacted, for example, the acid halide (such as the acid chloride), with an alkali salt metal (for example the sodium salt) of an appropriate sulfonamide, conveniently close to room temperature and in a suitable solvent or diluent, for example an ether, N, N-dimethylformamide or methylene chloride ·

When a salt compound of a compound of formula I is needed, it can be obtained by reaction with the appropriate base providing a physiologically acceptable cation, or by another conventional process ·

In addition, when an optically active form of a compound of formula I is required, one of the above processes is carried out using an optically active starting material. * Alternatively, the racemic form of a compound of formula I can be reacted. with an optically shaped

The activation of a suitable organic base, for example ephedrine, N, Ν, Ν-trimethyl (1-phenyl-ethyl) ammonium hydroxide or 1-phenyl-ethylamine, followed by conventional separation of the di-stereoisomeric mixture from the salts thus obtained, for example by fractional crystallization from a suitable solvent, for example alkanol (OpC ^) _} and the optically active form of said compound of formula 1 can then be released by treatment with an acid using a conventional procedure , for example, using an aqueous mineral acid such as dilute hydrochloric acid * λ most of the intermediates defined herein are new, for example the phenol derivatives of formula III, and are presented as separate and additional aspects of the invention *

As already mentioned, compounds of formula 1 are antagonists of one or more of the actions of TXÀg ', for example, certain of their actions on blood platelets, in the vascular system and / or in the lungs * Antagonism can be demonstrated by any of the following standard tests:

(a) The rabbit aorta strip model designed by £ iper and Va ne (Nature, 1969 _} 223, 29-35) or the model of aaz rat aorta strip developed by Kennedy and others (Prostaglandins, 1962 _}

- 11 24, 667-689) using the mimetic agent known as U46619 (described by HL Jones and others in Chemistry, Biochemistry and Fharmacological ^ ctivity the Frostanoids edited by S. liber Roberts and F. Scheinmann, on page 211 as an antagonist) ; Pergamon Press, 1979) can be used as an agonist; and w * (b) the blood platelet agglutination test based on Born's description (Nature, 1962, 194, 927-929) and which implies:

(i) the aggregation of platelet-rich and citrated human plasma, by adding TXAg mimetic agent U46619, in order to generate a dose-response curve;

(ii) the generation of a dose-response curve for U46619-stimulated basin segregation in the presence of increasing amounts of test compound (generally between 10 æl and 10 ’° H); ez * (iii) calculation of a Kg value that indicates the potency of the test compound as a TXAg antagonizer weighted by various concentrations, from the calculated value of the 50% response to aggregation by U46619 in the presence and absence of the test; and (c) a bronchoconstriction test involving the measurement of inhibition by a test compound of bronchoconstriction induced in the anesthetized Konzett-Rossler model of anesthetized guinea pig (as modified by Collier and James, Brit * J. Pharmacol '. 1967, 30, 283-307); by intravenous administration of the U46619 mimetic agent TXAg, θ which implies:

(i) obtaining a cumulative dose-response curve for U46619-induced bronchoconstriction by intravenous administration of constant volumes of increasing concentrations of U46619 (0.2-4 ug / kg) in a physiological saline solution and expressing bronchoconstriction. 12 -construction as the theoretical maximum that can be obtained without air flow for the tested animal;

(ii) generation of a cumulative dose-response curve to U46619-induced bronchoconstriction at 30-minute intervals for hours after oral dosing with the test compound; and (iii) calculation of a dosage ratio for the test compound (that is, the concentration rate of U46619 necessary to cause 50% bronchoconstriction in the presence and absence of the

The test compound) that indicates the potency of the txa ₂ antagonism · antagonism of the effects of TXAg in the vascular system can be demonstrated, for example in rats, as follows:

(d) ϋ-nesteziam Male rats (Alderley strain? ark) with sodium pentobarbital and is controlled blood pressure in the carotid would art · 0 agent U46619 mimetic AAR ₂ is administered intravenously at 5 .mu.g / kg through the jugular vein to produce an increase in systolic blood pressure of 20-50 mm / Hg (2640-3970) pascal) the process is repeated twice to ensure an adequate response. Then the test compound is administered either intravenously (through the jugular vein) or orally (through a cannula) directly into the stomach of the animal stimulated with U46619, five minutes after dosing with the test compound and then successively every ten minutes. until the hypertensive effect of U46619 is no longer blocked.

furthermore, antagonism of the effects of ^TXA 2 can be demonstrated, for example, by assessing the effects of a test compound on blood platelet agglutination obtained after administration of a test compound to a

Animal tested, such as a rabbit, rat, India or dog pig, using standard procedures similar to those described in (a) · However, when studying the acted AT ^f tinamento of dog platelets is necessary to use a threshold predetermined concentration of the agglutination agent of pimethas adenosine diphosphate (about 0.4-1.2 χ 10 K) together with the mimetic agent ^ 46619 ·

By way of illustration, the compound described in example 5 presented below, has a Κ _Ώ value of 1.05 x 10 M in the product (b) above ·

In general, the other compounds of formula I exhibit the following levels of TXA2 antagonism properties in one or more of the aforementioned assays, for example assay (a) pAg 6.0; test (b) 1.0 x 10 h; trial (c) dosing ratio 5.2 hours after oral dosing at 10 mg / kg or less and / or trial (d), significant inhibition of U46619-induced hypertension for at least 1 hour after oral dosing at 25 mg / Kg or less, without any manifestation of toxicity in the tests (c) or (d).

As previously specified, the compounds of formula I can be used in therapy or in the prevention of diseases or adverse conditions in warm-blooded animals in which it is intended to antagonize one or more of the actions of TXAg. In general, a compound of formula I will be administered for this purpose, orally, rectally, intravenously, AF subcutaneously, intramuscularly or by inhalation, in order to administer a dose between 1.01- 5 mg / kg of body weight four times a day, varying with the route of administration, the severity of the condition and the size and age of the patient to be treated ·

The compounds of formula I will generally be used in the form of a pharmaceutical composition constituted by 14 -

- by a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined above, together with a pharmaceutically acceptable carrier or diluent · Such a composition is presented as an additional aspect of the present invention and can be in a variety dosage form · For example, it can be in the form of tablets, capsules, solutions or suspensions for oral administration; in the form of a suppository for rectal administration; in the form of a sterile solution for administration by intravenous or intramuscular injection; in the form of a suspension or solution for aerosol or fogging, for administration by inhalation; and in the form of a powder, together with solid, pharmaceutically acceptable inert diluents, such as lactose, for administration by insufflation

A »A

Pharmaceutical compositions can be obtained by conventional processes using pharmaceutically acceptable carriers or diluents well known in the art · Tablets and capsules for oral administration can be conveniently prepared with an enteric coating, consisting for example of cellulose phthalate, to minimize the contact / __ f A of the active ingredient of formula I with stomach acids.

Af A 'h-s pharmaceutical compositions of this

The invention may also contain one or more known agents that are valuable for the treatment of said conditions or diseases; for example, it may be useful that a known platelet agglutination inhibitor AI, a hypolipidemic agent, an antihypertensive agent, a beta-adrenergic blocking agent or AI a vasodilator are present in a pharmaceutical composition of the invention for use in the treatment of a condition or a heart or vascular disease. Similarly, it may also be useful to have, for example, an antihistamine, a steroid (such as beclomethasone dipropionate), sodium chromoglycate, a phospho-diesterase inhibitor or a be • adrenergic stimulator in a pharmaceutical composition of the invention for

/ - use in the treatment of a cardiac or vascular condition or disease - A similar way can also be useful if, for example, an antihistamine, a steroid (such as beclomethasone dipropionate), sodium chromoglycate, a phospho-diesterase inhibitor or beta-adrenergic stimulator, in a pharmaceutical composition of the invention for use in the treatment of a lung condition or disease. A composition according to the invention can also advantageously contain a thromboxane A ₂ synthase inhibitor, for example example dazoxibem or furegrelato (U63557).

In addition to their use in therapeutic medicine, the compounds of formula I are also useful as pharmacological instruments for the development and standardization of assay systems for the evaluation of the effects of TXAg ⁱⁿ more laboratories such as cats, dogs, rabbits, monkeys, rats and rats, in the field of research of new therapeutic agents · The compounds of formula I can also be used due to their de ^ antagonizing properties, helping to maintain the flow of blood and the unblocking of blood vessels in blood animals (or corresponding parts) subjected to artificial cardiopulmonary bypass, for example during the transplantation of limbs or organs · When using a compound of formula I or a physiologically acceptable salt for this purpose, administration will be done in order to achieve a stationary concentration between, for example 0.1 and 10 mg per liter in san gue · t>. the present invention will now be illustrated with the following non-limiting examples in which, unless otherwise specified:

(i) evaporations are carried out by rotary evaporation in vacuo;

(ii) operations are carried out at room temperature, that is, between 18_26 ° C θ over a

- atmosphere of inert gas such as argon;

(iii) intermittent column chromatography was carried out in a Merck Kieselgel apparatus (Art. 93θ5) obtained from E. Merck, Darmstadt, W. Germany;

(iv) yields are shown for illustration only and are not necessarily the maximum achievable;

(v) the proton NMR spectra were normally determined at 90 or 200 MH _Z in CDGi ^ using tetra-methyl silane (TMS) as an internal standard and expressed as chemical shifts (delta values) in parts per million relative -

I TMS using the conventional abbreviations for the designation of the main cycles: s, singlet; m, multiplet; t, triplet; br, width, d, doublet;

(vi) all final products were isolated as racemates.

Example 1

O-chloro-benzaldehyde ($ 0 mg) and 2-toluenesulfonic acid (2 mg) were added to a stirred solution of E- | -ethanesulfonyl-4 (Z) -6- (4-o-hydroxy-phenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl) -hexenamide (Á) (209 mg) in toluene (3 ml). The reaction mixture was stirred for 1.5 hours and then purified by flash chromatography on silica, using hexane / ethyl acetate / acetic acid 50: 50: 1 (by volume) as eluents. N-ethane-sulfonyl-4 (Z) -6- / 2,4,5-cis) 7-2-o-chloro-phenyl-4-o-hydroxy-phenyl-1,3-dioxan-5-yl ) -hexenamide, as an oil (95 mg, 38%); EKR: 1.25 (3H, t), 1.82 (1H, m) 2.00 (1H, m.), 2.30 (4H, m), 2.75 (1H, m), 3.40 (2H, q), 4.2 (2H, m) 5.41 (3H, m), 6.05 (1H, s), 7.15 (7H, m) and 7.72 (1H, _m ).

The starting sulfonamide λ was obtained as follows:

• (i) Π, Μ '-dicyclohexyl-carbo- • -diimide (824 mg) was added to a stirred solution of acid 4 (Z) -6- (4-o- 17 -

- -methoxy-phenyl-2,2-dimethyl-1.3-dioxan-cis-5-yl) -hexenoic (1,336g) of 4- (dimethyl-amino) -pyridine (508 mg) and ethane-sulfonamide (436 mg ) in dichloromethane (45 ml) · The solid which formed was collected by filtration. The filtrate was evaporated. The residual oil was purified by flash chromatography on silica, using toluene / ethyl acetate / acetic acid 80; 20/2 (by volume) as the eluent, to provide K-ethanesulfonyl-4 (Z) -6- ( 4-o-methoxy-phenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl) -hexenamide (B) as a colorless oil (1.26g; 74%); I®íR: 1.36 (3H, t), 1.60 (6H, s) 1.65 (1H, m), 1.85 (1H, m), 2.55 (5H, m), 3 · 45 (2H, q) I 3.75 (1H , dd), 3.85 (3H, s), 4.2 (1H, dt), 5.32 (3H, m), 6.92 (2H, _m ), 7.26 (1H, m) and 7 * 55 (1H, m).

(ii) To a solution of B (1,114g) in 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DIaPU) (27 ml) was added sodium hydride (778 mg, 50% w / w dispersion in mineral oil) at a temperature between 0-5 ° C. After 3 minutes, ethane-thiol (1.004 ml) was added dropwise over 5 minutes · The mixture was maintained at 0-5 ° C for 5 minutes and then heated to 95 ^° C for 6 minutes hours. The cooled mixture was diluted with water (60 ml) and extracted with dichloromethane (5 x 50 ml). The aqueous phase was acidified to pH4 I with acetic acid and extracted with ether (3 x 50 ml) · The extracts were washed with a saturated saline solution (2 x 50 ml, dried (MgSO4) and evaporated The oil obtained was purified by flash chromatography on silica, using hexane / ethyl acetate / acetic acid 50; 50; 1 (by volume) as the eluent, to provide N-ethane-sulfonyl-4 (2) -6 - (4-o-hydroxy-phenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl) -hexenamide (^ -) as a colorless oil (870 mg 78%), ΙΦ®: 1.38 (3Ξ, t), 1.60 (6E, s), 1.65 (1H, _m ), 1.85 (1H, m), 2.35 (4H, m), 2.70 (1H, m), 3.45 (1H, q) 3.82 (1H, dd), 4.18 (1H, dt), 5.38 (3H, m), 6.88 (3H, m), 7.15 (1H, m), 8.1 (1H, _m ) _and 8.3 (1Ξ, m) · * The father's own hexenoic acid * obtained ob1 was as follows:

Potassium t-butoxide (12.5%) was added

g) for 2 minutes, to a stirred suspension of (3-carboxy-propyl) -triphenylphosphonium bromide (23.6 g) in tetrahydrofuran (THl · ¹ ) (250 ml) at a temperature between 0-5 ° 0. The mixture was stirred at room temperature for 50 minutes and cooled to 0 ° C before the addition of (4-o-methoxy-2,2-dimethyl-1,3-dioxan-cis-5-yl) -acetaldehyde (5.9 g) for 5 minutes. The mixture was stirred for 45 minutes and water (50 ml) was added. The solvent was removed by evaporation. The residue was dissolved in water (250 ml). The solution was covered with ethyl acetate (3 x 100 ml) and then acidified to pH4 with acetic acid. The released oil was extracted with ethyl acetate (3 x 100 ml). These extracts were washed with a saturated saline solution (2 × 100 ml), dried (KgSO4) and evaporated to provide an oil. The oil was purified by flash chromatography on a silica column, eluting with toluene / ethyl acetate / acetic acid 60; : 20: 1 (by volume) to provide 4 (Z) -6- (4-o-methoxy-phenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl) -hexenoic acid in the form as a colorless solid (6.0 g, 82 $), mp $ 2-96 ⁰ C; mp 99-101 ° C after recrystallization from ethyl acetate / hexane); 11-3; 1.65 (8H, m), 2.35 (5H, m), 3 · θ5 (5H, m), 5 · 28 (5ΙΊ, m) and 7.1 (4H, m) ·

Example 2

Sodium hydride (205 mg, 50 µl w / w dispersion in mineral oil) was added to a stirred suspension of N-ethane ~ sulfonyl-4 (Z) -6 - (/ 2,4,5-cis-) 7-2-p-cyano-phenyl-4-o-methoxy-phenyl-1,3-dioxan-5-yl) -hexenamide) (0) (555 mg) in DE? U (8 ml) at a temperature between 0-5 ° C. After 5 minutes, ethane-thiol (260 mg) was added over 2 minutes · The mixture was kept at 0-5 ° C for 10 minutes and then heated to 9O-95 ° O for 4 hours. The cooled reaction mixture was diluted with water (20 ml) and extracted with dichloromethane (3 x 50 ml), the aqueous phase was acidified to pH4 with acetic acid and extracted with ether (4 x X 50 ml) ) · The extracts were washed with saturated saline

(2 χ 50 ml), dried (KG-SO ^) and evaporated · The oil obtained was purified by flash chromatography on silica, using dichloromethane / ethanol 97.5: 2.5 g / v as an eluent, to provide N-ethane-sulfonyl-4 (Z) -6 - (/ 2,4,5-cis 7-2-p-ethano-phenyl-4-o-hydroxy-phenyl-1,5- dioxan-5-yl) -hexenamide as a colorless solid (215 mg, 63%), mp 63-6 ° C; W 1.35 (3H, t), 1.90 (2H, m), 2.28 (4H, s), 2.60 (1H, m), 5 · 42 (2H, q), 4.16 (1H, d), 4.25 (1H, d ), 5.40 (5H, m), 5.78 (1H, _s ), 6.9O (1H, m) 7.15 (2H, m), 7.70 (4H, q) and 7.96 (1H, s); m / e: 484 (M ⁺ ).

| The starting sulfonamide C was obtained as follows:

(i) A solution of 4 (Z) -6- (4-o-methoxy-phenyl-2,2-dimethyl ^ 1,5-dioxan-cis-5-yl) was heated at 105 ° C for 1 hour ) -hexenoic (66Umg), p-cyano-benzaldehyde (500mg) and p-toluenesulfonic acid (5 mg) in toluene (9 ml). The cooled reaction mixture was purified by flash chromatography on silica, using 95: 5 g / v dichloromethane / ethanol as eluent to provide 4 (Z) -6 - (/ 2,4,5-cis 7-2- acid) p-cyano-phenyl-4-o-methoxy-phenyl-1,5-dioxan-5-yl) -hexenoic, as a colorless solid (470 mg, 57%), mp 110-113 ° 0; 1.65 (1H, m), 1.98 (1H, m), 2.25 (4H, m), 2.45 (1H, m), 5.82 (2H, s)> 4.12 (1H, dt), 4.22 (1H, dt), 5.50 (3H, m), 5.78 (1H, _s ), 6.90 (2H, _m ), 7.25 (1H, m), 7.42 (1H, m) and 7.69 (4H, s).

(ii) 4- (Dimethyl-amino) -pyridine (150 mg), ethane-sulfonamide (116 mg) and H, U-dicyclohexyl-carbo-diimide (218 mg) were added to a stirred solution of D (452 mg) in dichloromethane (12 ml). Stirring was continued for 2 hours. Then the reaction mixture was cooled to 0 ° C and ether (50 ml) was added. The solid that formed was separated by filtration · The filtrate was evaporated and the residue was purified by flash chromatography on silica, using dichloromethane / ethanol 97.5: 2.5 g / v to provide N-ethanesulfonyl- 4 (Z) -6 - (/ ~ 2,4,5-. -Is _7-2-p-cyano-phenyl-4-o-methoxy-phenyl-1,5-dioxan-5-yl) -hexenamide ( C) as a colorless solid (585 mg; 73%), mp ·

154-156 ° C; BIR; 1.33 (3H, t), 165 (1H, m), 2.0

(4H, _m ), 2.52 (1H, _m ), 3 · 37 (2H, q), 3-63 (3H, s), 4.2 (2H, s),

5.35 (3H, m), 5.79 (1H, _s ), 7.17 (4H, m) and 7.70 (4H, _s ).

Example 3

For 15 minutes ethane-thiol (0.67 ml) was added to a stirred suspension of sodium hydride (432 mg, 50% w / w oil dispersion) in DHPU (15 ml) at 4 ° C, kept under a water atmosphere. After 30 minutes, the temperature was raised to 85 ° C and N-methanesulfonyl-4 (Z) -6 - (/ ~ 2.4.5-cis _7-2-t-butyl-4-o was added -methoxy-phenyl-1,3-dioxan-5-yl) -hexanamide (659 mg). The mixture was stirred for 3 hours, then cooled to 10 ° C and poured into a mixture of ice and water (60 ml). The aqueous mixture was washed with dichloromethane (2 x 30 ml) · The aqueous phase was acidified with acetic acid and extracted with ether (3 x 30 ml) · The extracts were washed with water (2 x 20 ml) ml), and with a saturated saline solution (2 x 20 ml), then dried (MgSO4) and evaporated.

flash chromatography using hexane / ethyl acetate / acetic acid 70: 30: 1 (by volume) as the eluent to provide an oil which crystallized on standing, providing D-methanesulfonyl-4 (2) -6 - (/ 2,4,5-cis _7-2-t-butyl-4-o-hydroxy-phenyl · —1,3-dioxan-5-yl) -hexenamide (318 mg) mp 142-143.5 ° C; WR;

1.01 (9H, s), 1.67 (1H, m), 1.89 (1H, m) 2.32 (4H, m), 2.59 (1H, m), 3.28 (3H, s), 3.90 (1H, dm J = 11H _Z ), 4.10 (1H, dd J = 11.1 H _Z ), 4.38 (1H, s), 5.22 (1H, d J = 2H _Z ), 5 · 38 (2H, _m ), 6.89 (2H, _m )

7.18 (1H, _m ); m / e 425 (M ⁺ ).

starting material was obtained as follows:

(i) A suspension of 4 (3) -6- (4-o-methoxy-phenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl) -hexenoic acid (1.88 g) ⁱⁿ 2,2-dimethyl-propionaldehyde (5 ml) with £ -toluenesulfonic acid (5 mg). The mixture was stirred for 18 hours and then ether (50 ml) was added. The mixture was extracted with

- 0.5 M potassium oxide (4x25 ml). The combined aqueous extracts were acidified to pH5 (acetic acid) and then extracted with ether (3 x 50 ml). The combined extracts were washed successively with water (2 x 50 ml) and saturated saline solution (50 ml), then dried (NgSO4) and evaporated. The residue was purified by I4PLC eluting with hexane / ethyl acetate) acetic acid (85: 15: 1 g / v) / A clear, Christian oil was obtained at rest to provide 4- (2) -6 acid - (/ _7-2 cis-2,4,5-t-butyl-4-o-methoxyphenyl-1,3-dioxan-5-yl) hexenoic acid (2.276 g) , mp 74-77 C ^c; 0.98 (9H, s), 1.51 (1H, m), 1.80 | (1H, m), 2.27 (4H, m), 2.45 (1H, _m ), 3.80 (3H, _s ), 3.85 (1H, dm

J = 11Hz), 4.02 (1H, dd, J = 11.1 H _z ), 4.37 (1H, s), 5.13 (1H, d J = 2H _Z ), 5.27 (2H, m), 6.83 (1H, dd J = 7.1H _Z ), 6.97 (1H, td J = = 7.1 Hz), 7.22 (1H, td J = 7, 1.5 Hz), 7.45 (1H, dd J = 7, 1.5H _Z ).

(ii) Ν, Ν'-dieiclohexyl-carbo-diimide (1.08 g) was added to a solution of acid 4 (Z) -6 - (/ “2,4,5-cis7 -2 -t-butyl-4-o-methoxy-phenyl-1,3-dioxan-5-yl) -liexenoic (1.81 g) of 4- (dimethyl-amino) __ pyridine (0.61 g) and methane- sulfonamide (0.48g) in dichloromethane (20 ml). The mixture was stirred for 1 hour at 4 ° C and then for 18 hours at room temperature · The Ν, Ν'-dicyclohexyl urea which precipitated was removed by filtration and washed with dichloromethane · 0 filtered and the washing products were extracted with 0.114 sodium hydroxide (50 ml). The alkaline extract was acidified with acetic acid and extracted with ether (3 x 30 ml). These extracts are washed with water (3 x 20 ml) and with a saturated saline solution (1 x 20 ml) then dried (NgSO4) and evaporated. The oil obtained was purified by flash chromatography, using hexane / ethyl acetate / acetic acid 75: 25: 1 (by volume) as eluent, to provide an oil which crystallized on standing, providing N-methylsulfonyl-4 ( 2) -6 - (/ 2,4,5-cis _7-2-t-butyl-4-o-methoxy-phenyl-1,3-dioxan-5-yl) -hexenamide (1, θ3 g) mp 146-148 ° C;

1.01 (9H, s), 1.49 (1H, m), 1.87 (1H, _m ), 2.40 (5 m), 3.27; (3H, _s ), 3.81 (3H, _s ), 3.90 (1H, dm <I = 11Hz), 4.05 (1Ή, dd = 11.1H _Z ), 4.39 (1E, s), 5.18 (1H, d J = 2Hz), 5.35 (2H, m), 6.86

Example 4

An illustrative dosage form of a composition of the present invention is provided for the following capsule formulation:

Claims (1)

Magnesium stearate mg / capsule 588.5 1.5 the capsules can conveniently be made of pure gelatin and are filled by a conventional process. Compound X * is a compound of formula I or a respective salt as defined above, for example the compound of Example 1, 2 or 3, or its pharmaceutically acceptable salt. - 1 * Process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof in which R is trifluoromethyl, alkyl), or phenyl which optionally supports a substituent selected from halogen, cy2 year, nitro, trifluorornethyl and alkoxy and R is (C C-Cg) alkyl, benzyl or phenyl, the latter two optionally being able to support a substituent chosen from halogen, (Cj-C ^) alkyl, trifluoromethyl alkoxy, cyano and nitro) and where the substituents in the positions 4 and 5 of the dioxane ring / i A / in formula I and the substituent R has cis-relative stereochemistry, characterized by: a) reacting an aldehyde of formula II where R is as previously defined, with a Wittig reagent of the formula: R « ₃ P = CH. (CH ₂ ) ₂ .CO.N ~ .S0 ₂ R ² K ⁺ where R * (C ^ -Cg) and M ⁺ is a suitable cation; is aryl or alkyl b) if a phenol derivative of formula III is deprotected where R ”is a suitable protecting group; c) reacting an erythro-diol derivative of formula IV in which Q or Q is hydrogen and the other is hydrogen or a group of the formula -CRaRb.OH in which Ra and Rb are the same or different from alkyl with an aldehyde of the formula R'.CO.H, or with a corresponding acetal, hemi-acetal or hydrate; or D) reacting a compound of formula V where Ra or Rb is hydrogen, methyl or ethyl and the other is methyl or ethyl, with an aldehyde of the formula R'.00.H or with a hemi-acetal acetal or hydrate corresponding in the presence of an acid catalyst; then, when an optically active form of a compound of formula I is desired, either one of the procedures from (a) to (d) above is performed using an optically active form of the appropriate starting material, or the racemic form is resolved using a suitable optically active base and when a pharmaceutically acceptable salt is desired, the free acid form of the compound of formula I is reacted with a suitable base providing a physiologically acceptable cation; and where R and R are as previously defined. _2. Process according to claim 1, characterized in that in formula III R and R have the above meanings and R is alkyl (O 0 -Cg), acyl, allyl, tetrahydropyran-2-yl or trimethylsilyl. s> a M) Μ MBt Process according to claim 1, characterized in that R is trifluoromethyl, isopropyl, isobutyl, 26 sec-butyl or t-butyl, or be phenyl which optionally supports a substituent selected from fluorine, chlorine, bromine, carbon dioxide, nitro, trifluoromethyl, methoxy and ethoxy; and R is methyl, ethyl, propyl, benzyl, or phenyl, the latter two optionally bearing a substituent selected from fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, cyano and nitro · Process according to claim 1 or 3, characterized in that R is isopropyl, t-butyl, or trifluoromethyl, or is phenyl which optionally supports a substituent selected from fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl and methoxy. Process according to claim 1 or 3, characterized in that R is isopropyl, t-butyl, trifluoromethyl, 2-chlorophenyl, 2-cyanophenyl, 3- (trifluoromethyl) phenyl, 4-chlorophenyl, 4-cyanophenyl or 4-nitrophenyl. Process according to claims 1 to 5, characterized in that R is methyl or ethyl. Process according to claim 1, characterized by obtaining N ~ ethane-sulfonyl-4 (Z) -6 - (/ “2,4,5-cis _7-2-0-chlorophenyl-4-0-hydroxyphenyl-1,3-dioxan-5 -yl) -hexene mide, 1T-ethanesulfonyl-4 (Z) -6 - (/ 2,4,5-cis_7-2-p.-cyanophenyl-4-0-hydroxyphenyl-1,3-dioxan-5-yl ) hexenamide, h-methanesulfonyl-4 (Z) -6 - (/ 2,4,5-cis_7-2-t-butyl-4-0-hydroxyphenyl-1,3-dioxan-5-yl) he - 27 xenamide, or a corresponding pharmaceutically acceptable salt · - Process according to the preceding claims, characterized in that a salt chosen is obtained from alkali metal, alkaline earth metal, aluminum and ammonium / ammonium salts and from salts with organic amines and ouaternary bases that form physiologically acceptable cations · -9â - Process for the preparation of a compound, The pharmaceutical section characterized by incorporating a compound of formula I as an active ingredient when prepared according to claim 1 in association with a pharmaceutically acceptable carrier or diluent. - yoyo - Process according to claim 9, characterized in that an thromboxane synthase inhibitor Ag. the applicant declares that the first application for this patent was filed in the United Kingdom on Kaio 8, 1986 _S ob on ⁰ · 8611174.